Novel subtype-specific prognostic associations of KRAS and BRAF mutations revealed in colorectal cancer

First author Jørgen Smeby with co-author Ina A. Eilertsen
First author Jørgen Smeby with co-author Ina A. Eilertsen

In a recent publication in Annals of Oncology (journal impact factor 11.9) by Jørgen Smeby and colleagues in the Lothe lab at the Department of Molecular Oncology, integration of gene expression-based subtyping and microsatellite instability status led to discovery of novel subtype-specific prognostic associations of the thoroughly investigated KRAS and BRAFV600E mutations in primary colorectal cancer (CRC).

Despite considerable efforts to identify molecular biomarkers in CRC few have reached clinical implementation. This can be explained by CRC being a heterogeneous disease with large variation in clinical outcome and molecular characteristics. CRC can, based on their patterns of genomic instability, be divided into those exhibiting microsatellite instability (MSI) and those that do not (microsatellite stable, MSS). The consensus molecular subtypes (CMS) of CRC represent a novel gene expression-based stratification framework identifying molecularly and clinically distinct subgroups, enabling analysis of subtype-specific significance of cancer-critical biomarkers.

The study investigated the distribution and prognostic impact of KRAS and BRAFV600E mutations according to MSI status and CMS groups. The analysis included 1197 patients with CRC stages I-IV from a prospective series from Oslo University Hospital, supplemented with data from a French multi-centre cohort. KRAS mutations were shown to be associated with poor prognosis exclusively in MSS tumors with CMS2/CMS3 epithelial-like gene expression profiles. In contrast, BRAFV600E displayed strong enrichment and significant poor prognostic value limited to CMS1 MSS tumors. These subtype-specific prognostic associations were biologically substantiated by differential effects of BRAFV600E and KRAS mutations on their corresponding gene expression signatures, according to MSI status and CMS group.

The results highlight the relevance of interpreting the prognostic and predictive value of molecular aberrations within biological homogenous subtypes of CRC.


The article Annals of Oncology article:

CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer.
Smeby J, Sveen A, Merok MA, Danielsen SA, Eilertsen IA, Guren MG, Dienstmann R, Nesbakken A, Lothe RA.
Ann Oncol. 2018 Mar 5. doi: 10.1093/annonc/mdy085. [Epub ahead of print]
PMID: 29518181

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